ISOXAZOLE AND PYRAZOLE DERIVATIVES AS DOPAMINE RECEPTOR SUBTYPE LIGANDS

Abstract: A class of substituted isoxazole and pyrazole derivatives of formula (I), or a salt thereof or a prodrug thereof, wherein the broken circle represents two non-adjacent double bonds whereby the five-membered ring containing X and Y is aromatic; one of X and Y represents nitrogen, and the other of X and Y represents oxygen or N-R<5>; R<1> represents hydrogen, C1-6 alkyl or trifluoromethyl; R<2> and R<3> independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR<a>, -SR<a>, -SOR<a>, -SO2R<a>, -SO2NR<a>R<b>, -NR<a>R<b>, -NR<a>COR<b>, -NR<a>CO2R<b>, -COR<a>, -CO2R<a> or -CONR<a>R<b>; R<4> represents hydrocarbon or a heterocyclic group; R<5> represents hydrogen or C1-6 alkyl; and R<a> and R<b> independently represent hydrogen, hydrocarbon or a heterocyclic group, are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment and/or prevention of disorders of the dopamine system, in particular schizophrenia.

Description: ISOXAZOLE AND PYRAZOLE DERIVATIVES AS DOPAMINE RECEPTOR SUBTYPE LIGANDS This invention relates to a particular class of substituted isoxazole and pyrazole derivatives which are ligands for dopamine receptor subtypes within the body and are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, and disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea. Upper gastrointestinal tract motility is believed to be under the control of the dopamine system. The compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying. Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds capable of counteracting this effect, including the compounds in accordance with the present invention, may accordingly be of value in the prevention or reduction of dependence on a dependence-inducing agent. Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This implies that the compounds of the present invention may be beneficial in controlling vascular blood flow. The localisation of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the present invention may therefore be of assistance in the prevention and/or treatment of such conditions as hypertension and congestive heart failure. Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D^ receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D 2 receptor subtype, and at least one form of the D3 receptor subtype, have also been discovered. More recently, the D4 (Van Tol et al. , Nature (London) , 1991, 350, 610) and D 5 (Sunahara et aJL. , Nature (London), 1991, 350, 614) receptor subtypes have been described. The compounds in accordance with the present invention, being ligands for dopamine receptor subtypes within the body, are accordingly of use in the treatment and/or prevention of disorders of the dopamine system. The present invention accordingly provides a compound of formula I, or a salt thereof or a prodrug thereof: ( I) wherein the broken circle represents two non-adjacent double bonds whereby the five-membered ring containing X and Y is aromatic; one of X and Y represents nitrogen, and the other of X and Y represents oxygen or N-R 5 ; R 1 represents hydrogen, C^g alkyl or trifluoromethyl; R 2 and R 3 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -S0 2 R a , -S0 2 NR a R b , -NR a R b , -NR a COR b , -NR a C0 2 R b , -COR a , -C0 2 R a or -CONR a R b ; R^ represents hydrocarbon or a heterocyclic group; R 5 represents hydrogen or C^g alkyl; and R a and R independently represent hydrogen, hydrocarbon or a heterocyclic group. For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, εuccinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include Cι_g alkyl, C 2 _g alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 cycloalkyl, C 3 _ 7 cycloalkyl(C 1 _ 6 )alkyl, aryl and aryl (Cι_g)alkyl. The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroato preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C 3 _ 7 heterocycloalkyl, C3-.7 heterocycloalkyl (Ci-g) alkyl, heteroaryl and heteroaryl (C^g)alkyl groups. Suitable alkyl groups include straight- chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Suitable alkenyl groups include straight- chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups. Suitable alkynyl groups include straight- chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups. Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl. Particular aryl groups include phenyl and naphthyl. Particular aryl (C^-g)alkyl groups include benzyl, naphthylmethyl, phenethyl and phenylpropyl. Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl groups. Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, indolyl, aza-indolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. Particular heteroaryl (C 1 _g) alkyl groups include pyridylmethyl, pyrazinyl ethyl , indolylmethyl and aza- indolylmethyl. The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from C^g alkyl, adamantyl , phenyl, aryl ( ^-Q ) alkyl, halogen, C^- haloalkyl, C^-g aminoalkyl, trifluoromethyl, hydroxy, C 1 _g alkoxy, aryloxy, keto, Cι_3 alkylenedioxy, nitro, cyano, carboxy, C 2 _g alkoxycarbonyl, C 2 _g alkoxycarbonyl (C 1 _g) alkyl, C 2 _g alkylcarbonyloxy, arylcarbonyloxy, C _g alkylcarbonyl, arylcarbonyl, C j -.g alkylthio, C^-g alkylsulphinyl, C^g alkylsulphonyl, arylsulphonyl, trifluoromethane- sulphonyloxy, -NR V R W , -NR v COR w , -NR v C0 2 R w , -NR v S0 2 R w , -CH 2 NR v S0 2 R w , -NHCONR v R w , -PO (OR v ) (OR w ) , -CONR v R w , -S0 2 NR v R w and -CH 2 S0 2 NR v R w , in which R v and R w independently represent hydrogen, Cη__g alkyl, aryl or aryl (Cτ__ 6 ) alkyl. The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially chlorine. The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I . Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomerε. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. As will be appreciated, the five-me bered heteroaromatic ring containing the moieties X and Y in formula I above is a substituted isoxazole or pyrazole ring. Suitable values for the substituent R 1 include hydrogen, methyl and ethyl, especially methyl. Suitable values for the substituents R 2 and R 3 include hydrogen, halogen, cyano, trifluoromethyl, nitro, amino, C^g alkylamino, di(C 1 _g)alkylamino, C j _g alkyl, Cι . _ alkoxy, aryl (C^g) alkoxy and C _ 6 alkylcarbonyl. Particular values include hydrogen, methyl, ethyl, isopropyl, nitro, methoxy and chloro. Suitably, at least one of R r> and R * _ is hydrogen. Suitable values for the substituent R 4 include aryl (Cι_ )alkyl and heteroaryl (Cη ^ .g)alkyl, any of which groups may be optionally substituted. Examples of suitable substituents on the group R 4 include ~ ~_- alkyl, halogen, Cχ_g alkoxy and nitro. Particular values of R 4 include benzyl, methyl- benzyl, chlorobenzyl, dichlorobenzyl, methoxy-benzyl, nitro-benzyl, naphthylmethyl, phenethyl, phenylpropyl, pyridylmethyl and aza-indolylmethyl. Suitably, R 5 is hydrogen or methyl. A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof: - 1 - 12 ( I IA) wherein R 1 is as defined with reference to formula I above; X 1 represents oxygen or N-R 5 in which R 5 is as defined with reference to formula I above; R 12 represents hydrogen, halogen, cyano, trifluoromethyl, nitro, amino, C j -g alkylamino, di(C 1 _g) alkylamino, C^g alkyl, C^-g alkoxy, aryl (C^- ) alkoxy or C 2 _g alkylcarbonyl; n is 1, 2, 3 or 4, preferably 1; and W represents a group of formula (i) or (ii) : ( i ) ( ϋ) in which Z represents nitrogen or CH; and R 16 represents hydrogen, halogen, nitro, C^g alkyl or C^- alkoxy. Particular values of R with reference to formula IIA above include hydrogen, methyl, ethyl, isopropyl, nitro, methoxy and chloro. Suitably, X is oxygen, NH or N-methyl. Particular values of R 16 include hydrogen, chloro, nitro, methyl and methoxy. Another sub-class of compounds according to the invention is represented by the compounds of formula IIB, and salts and prodrugs thereof: ( I I B) wherein R is as defined with reference to formula I above; Y 1 represents oxygen or N-R 5 in which R 5 is as defined with reference to formula I above; and R~ ~ , n and W are as defined with reference to formula IIA above. Suitably, Y 1 is oxygen, NH or N-methyl. Specific compounds within the scope of the present invention include: l-benzyl-4-(5-methyl-4-phenyl-lH-pyrazol-3-ylmethyl) - piperazine; l-benzyl-4-(5-ethyl-4-phenyl-lH-pyrazol-3-ylmethyl)- piperazine; l-benzyl-4-(4-phenyl-lH-pyrazol-3-ylmethyl)piperazine; l-(4-chlorobenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; 1-(4-methoxybenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; l-(2-phenylethyl)-4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; 3-[4-(5-methyl-4-phenyl-lH-pyrazol-3-ylmethyl)piperazin- l-ylmethyl]-lH-pyrrolo[2,3-b]pyridine; l-benzyl-4-(l,3-dimethyl-4-phenyl-lH-pyrazol-5-ylmethyl)- piperazine; l-benzyl-4-(l-methyl-4-phenyl-lH-pyrazol-3-ylmethyl)- piperazine; l-benzyl-4-(2-methyl-4-phenyl-2H-pyrazol-3-ylmethyl)- piperazine; l-benzyl-4-(5(3) -methyl-4-phenylisoxazol-3 (5) -ylmethyl) - piperazine; l-benzyl-4-[4-(4-chlorophenyl)-5-methyl-lH-pyrazol-3- yl ethyl]piperazine; l-benzyl-4-[5-methyl-4-(2-methylphenyl) -lH-pyrazol-3- yl ethyl]piperazine; 1-(3-chlorobenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; l-(2-methylbenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; l-(2-chlorobenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; l-(pyridin-4-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; 1-(pyridin-3-ylmethyl) -A-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; 1-(pyridin-2-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; l-benzyl-4-[4-(2-methylphenyl) -lH-pyrazol-3-ylmethyl]- piperazine; l-(2-chlorobenzyl) -4-(5(3)-methyl-4-phenylisoxazol-3 (5) - ylmethyl)piperazine; l-(2-methylbenzyl) -4-(5 (3) -methyl-4-phenylisoxazol-3 (5) - ylmethyl)piperazine; l-(pyridin-3-ylmethyl) -4-(5(3) -methyl-4-phenylisoxazol- 3 (5) -ylmethyl)piperazine; l-(4-methylbenzyl) -4-[5-methyl-4-(2-methylphenyl) -1H- pyrazol-3-ylmethyl]piperazine; l-(4-methylbenzyl)-4-[5(3)-methyl-4-(2- methylphenyl) isoxazol-3 (5) -ylmethyl]piperazine; and salts and prodrugs thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin. In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 g/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV: ( I I I ) ( IV) wherein R 1 , R 2 and R 3 are as defined above, R 40 corresponds to the group R as defined above or represents an amino-protecting group, and X a represents oxygen or N-R in which R is as defined above; followed, where necessary, by removal of the amino-protecting group R 40 and subsequent attachment of the substituent R 4 . Where X a represents N-R 5 , the reaction is conveniently carried out by stirring the reactants in a suitable solvent, for example a Cι- 4 alkanol such as methanol. Where X a represents oxygen, the reaction is typically effected by stirring the reactants in N,N- dimethylformamide, suitably in the presence of a non- nucleophilic base such as ethyldiisopropylamine. Depending upon the nature of the reactants and of the chosen reaction conditions, the reaction may afford the desired product in a single step, or may proceed via a hydroxy intermediate which requires dehydration to convert it into the corresponding product of formula I. The dehydration step may be effected by converting the hydroxy moiety into a leaving group, suitably by treatment with methanesulphonyl chloride and triethylamine in an appropriate solvent such as dichloromethane. Where the substituent R represents an amino- protecting group, this group is suitably an alkoxycarbonyl moiety such as t-butoxycarbonyl (BOC) , which can conveniently be removed as necessary by treatment under acidic conditions, e.g. stirring in trifluoroacetic acid. The subsequent attachment of the R 4 substituent may suitably be accomplished by conventional means including N-alkylation, where R 4 represents, for example, an alkyl or aryl-alkyl group. Typical N-alkylation conditions comprise treating the deprotected amine with an alkyl or aryl-alkyl halide, such as methyl iodide or phenethyl bromide, suitably under basic conditions, e.g. ethyldiisopropylamine in N,N-dimethylformamide. Alternatively, where R 4 represents an indol-3-ylmethyl moiety or an aza-analogue thereof, e.g. 7-azaindol-3- ylmethyl, the N-alkylation reaction can conveniently be effected by heating the deprotected piperazine precursor with a gra ine or 7-azagramine derivative in toluene at reflux. As will be appreciated, the overall reaction between compounds III and IV will often give rise to a mixture of isomeric products of formula I, in one of which X represents nitrogen and Y represents oxygen or N-R 5 , and in the other of which the X and Y moieties are reversed. For this reason, it will generally be necessary at an appropriate stage to separate the mixture of isomers obtained therefrom by conventional methods such as column chromatography. The intermediates of formula III above may be prepared by reacting a carboxylic acid of formula R -C0 2 H, or an activated derivative thereof, with a metal enolate of formula V: 0 ( V ) wherein R 2 , R 3 and R 40 are as defined above, and M represents a metal capable of providing a suitable counterion for the enolate anion. The metal M is suitably an alkali metal, especially lithium. The activated derivative of the carboxylic acid R -C0 2 H is suitably the compound formed by reaction between the carboxylic acid R 1 -C0 2 H and 1,1*- carbonyldiimidazole, typically in tetrahydrofuran at room temperature. The reaction between the carboxylic acid R -C0 2 H, or the activated derivative thereof, and compound V is suitably carried out in a solvent such as tetrahydrofuran, typically commencing at -78"C with warming to room temperature. The metal enolate of formula V is suitably prepared by reacting the corresponding ketone of formula VI: (V I ) wherein R , R and R 40 are as defined above; with a strong base such as lithium hexamethyldisilazide, typically in tetrahydrofuran at -78"C. The intermediates of formula VI may be prepared by reacting a compound of formula VII with a compound of formula VIII: (VI I ) (VI M) wherein R 2 , R 3 and R 40 are as defined above, and L represents a suitable leaving group. The leaving group L is suitably a halogen atom, e.g. chlorine, in which case the reaction is conveniently carried out by stirring the reactants under basic conditions in a suitable solvent, e.g. triethylamine in dichloro ethane. Where they are not commercially available, the starting materials of formula VII and VIII may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art. Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+) -di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The following Examples illustrate the preparation of compounds according to the invention. The compounds useful in this invention potently inhibit [ 3 H]-spiperone binding to human dopamine D 4 receptor subtypes expressed in clonal cell lines. [ 3 H]-Spiperone Binding Studies Clonal cell lines expressing the human dopamine D 4 receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mM MgS0 4 for 20 min on ice. Membranes were centrifuged at 50,000g for 15 min at 4*C and the resulting pellets resuspended in assay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, 1.5 mM CaCl 2 , 5 mM MgCl 2 , 5 mM KCl, 120 mM NaCl, and 0.1% ascorbic acid) at 20 mg/ml wet weight. Incubations were carried out for 60 min at room temperature (22°C) in the presence of 0.05-2 nM [ 3 H]-spiperone or 0.2 nM for displacement studies and were initiated by addition of 20-100 μg protein in a final assay volume of 0.5 ml. The incubation was terminated by rapid filtration over GF/B filters presoaked in 0.3% PEI and washed with 10 ml ice- cold 50 mM Tris-HCl, pH 7.4. Specific binding was determined by 10 μM apomorphine and radioactivity determined by counting in a LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant K^ could be calculated for each test compound. The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [ H]-spiperone from the human dopamine D 4 receptor subtype of below 1.5 μM. EXAMPLE 1 l-Benzyl-4-(5-methyl-4-phenyl-lH-pyrazol-3-ylmethyl, - piperazine bis hydrogen oxalate Step A: 1-(4-Benzylpiperazin-l-yl) -3-phenyl-propan-2-one To a solution of l-chloro-3-phenyl-propan-2-one (lOg, 59mmol) in dichloro ethane (100ml) was added benzylpiperazine (12.3ml, 71mmol) and triethylamine (8.2ml, 59mmol) . The yellow solution was stirred overnight at ambient temperature and water was added (50ml) . The organic phase was decanted, washed with brine (50ml) , dried (sodium sulphate) and evaporated. The residue was purified by column chromatography on silica using petroleum ether (60-80)/ethyl acetate to afford a yellow oil (2.4g, 13%). 1 H NMR (250MHz, CDC1 3 ) δ 2.30-2.64 (8H, m) , 3.19 (2H, s) , 3.51 (2H, s) , 3.74 (2H, s) , 7.17-7.38 (10H, m) . Step B: 1-.4-BenzylpJperazin-l-yl) -3-phenyl-pentan-2.4- dione Acetic acid (0.75ml, 13mmol) was added to a stirred solution of N,N'-carbonyldiimidazole (2.1g, 13mmol) in anhydrous tetrahydrofuran (50ml) . After 30 minutes at ambient temperature a solution of 1-(4-benzylpiperazin-l- yl) -3-phenyl-propan-2-one (2g, 6.5mmol) in anhydrous tetrahydrofuran (50ml) was added. The solution was cooled to -78°C and lithium bis(trimethylsilyl)amide (IM in tetrahydrofuran, 13ml) was added dropwise. The resulting mixture was stirred for 45 minutes at -78°C, overnight at room temperature and quenched with a saturated aqueous ammonium chloride solution. The organic layer was separated, dried (sodium sulphate) and evaporated. The residue was purified by column chromatography on silica using petroleum ether (60- 80)/ethyl acetate, to afford the required product as an oil (530mg, 23%) . ^-H NMR (250MHz, CDC1 3 ) δ 1.86 (3H, s) , 2.37-2.52 (8H, m) , 3.01 (2H, s) , 3.58 (2H, s) , 7.08- 7.45(10H, m) . Step C: l-Benzyl-4-C5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine bis hydrogen oxalate To a solution of the foregoing diketone (330mg, 0.94mmol) in ethanol (15ml) was added hydrazine hydrate (0.55ml, 9.4mmol) . The solution was stirred at room temperature for 1 hour and evaporated. Dichloromethane (20ml) and 10% sodium hydroxide solution in water (20ml) were added to the residue. The organic layer was separated and the aqueous extracted with dichloro ethane (20ml) . The combined organics were dried (sodium sulphate) and evaporated to give the title compound free base as a gum (310mg, 95%) . The bis hydrogen oxalate salt had p 226- 230°C. λ E NMR (360MHz, DMSO) <5 2.23 (3H, s) , 2.62-2.80 (8H, m) , 3.70-3.92 (4H, s) , 7.26-7.47 (10H, m) . MS, CI + m/z = 347 for (M+H) + . Found: C, 58.80; H, 5.45; N, 10.33. C 22 H 26 N 4 .2(CO 2 H) 2 .0.25H 2 O requires C, 58.80; H, 5.79; N, 10.55%. EXAMPLE 2 l-Benzyl-4-(5-ethyl-4-phenyl-lH-pyrazol-3-ylmethyl)- piperazine bis hydrogen oxalate Carrying out Steps la-c whilst replacing acetic acid in Step lb with propionic acid afforded the titled compound as a solid. mp 224-227°C. ^-H NMR (360MHz, DMSO) δ 1.12 (3H, t, J = 7.5Hz), 2.61 (2H, q, J = 7.5Hz), 2.70-2.96 (8H, m) , 3.76 (2H, s) , 3.87 (2H, s) , 7.26-7.48 (10H, m) . MS, CI + m/z = 360 for (M+H) + . Found: C, 58.80; H, 5.80; N, 9.93. C 23 H 28 N 4 .2 (C0 2 H) 2 .0.5H 2 0 requires C, 59.01; H, 6.05; N, 10.19%. EXAMPLE 3 l-Benzyl-4- (4-phenyl-lH-pyrazol-3-ylmethyl) -piperazine bis hydrogen oxalate Carrying out Steps la-c whilst replacing acetic acid in Step lb with formic acid afforded the titled compound as a solid. mp 226-228°C. 1 H NMR (360MHz, DMSO) δ 2.66- 3.05 (8H, m) , 3.80 (2H, ε) , 4.02 (2H, s) , 7.22-7.62 (10H, m) , 7.94 (1H, s) . MS, CI + m/z = 333 for (M+H) + . Found: C, 57.34; H, 5.92; N, 10.29. C 21 H 24 N 4 .2 (C0 2 H) 2 .H 2 0 requires C, 57.50; H, 5.45; N, 10.41%. EXAMPLE 4 1- (4-Chlorobenzyl. -4- .5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl, -piperazine bis hydrogen oxalate Step A: 4- .4-Chlorobenzyl) -piperazin-1-carboxylic acid tert-butylester To a solution of 4-chlorobenzyl chloride (1.73g, 10.7mmol) in ethanol (30ml) was added tert-butyl-1- piperazine carboxylate (2g, 10.7mmol) and potassium carbonate (3g, 21.4mmol) . The mixture was heated to reflux overnight and the solvent removed. The residue was partitioned between water (50ml) and dichloromethane (50ml) . The organic layer was separated, dried (sodium sulphate) and evaporated to give the required ester as an oil (3.1g, 93%) . Η. NMR (360MHz, CDC13) δ 1.45 (9H, s) , 2.33-2.41 (4H, m) , 3.38-3.45 (4H, m) , 3.46 (2H, s) , 7.21- 7.31 (4H, m) . MS, CI + m/z = 311 for (M+H) + . Step B: 1- .4-Chlorobenzyl) -piperazine To a solution of the foregoing protected piperazine (3g, 9.7mmol) in dichloromethane (30ml) was added trifluoroacetic acid (7.7ml, 97mmol) . The solution was stirred at ambient temperature overnight, evaporated and the residue partitioned between a 10% solution of potassium carbonate in water (50ml) and ethyl acetate (50ml) . The organic layer was decanted and the aqueous phase was extracted with ethyl acetate (3 x 50ml) . The combined organics were dried (sodium sulphate) and evaporated to give the title product as a low melting solid (2g, 98%). 1 H NMR (250MHz, CDC1 3 ) δ 2.46-2.62 (4H, m) , 2.99-3.12 (4H, m) , 3.51 (2H, s) , 7.20-7.35 (4H, m) . Step C: l-(4-Chlorobenzyl)-4-f5-methyl-4-phenyl-lH- pyrazol-3-ylmethyl. -piperazine bis hydrogen oxalate The title compound was prepared following procedures described in Steps la-c using l-(4-chlorobenzyl)- piperazine instead of benzylpiperazine in Step la. mp 217-219°C. 1 H NMR (360MHz, DMSO) <S 2.23 (3H, s) , 2.60- 2.92 (8H, m) , 3.74 (2H, s) , 3.84 (2H, s) , 7.24-7.46 (9H, m) . MS, CI + m/z = 381 for (M+H) + . Found: C, 53.62; H, 5.27; N, 9.64. C 22 H 25 N 4 C1.2 (C0 2 H) 2 .H 2 0.requires C, 53.93; H, 5.40; N, 9.68%. EXAMPLE 5 1-(4-Methoxybenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine bis hydrogen oxalate Carrying out Steps 4a-c whilst replacing 4-chlorobenzyl chloride in Step 4a with 4-methoxybenzyl chloride afforded the titled compound as a solid. mp 222-224°C. 1 H NMR (360MHz, DMSO) δ 2.23 (3H, s) , 2.60-3.04 (8H, m) , 3.64 (2H, s) , 3.75 (3H, s) , 3.97 (2H, s) , 6.95-7.47 (9H, m) . MS, CI + m/z = 377 for (M+H) + . Found: C, 56.53; H, 5.82; N, 9.86. C 2 3H 28 N 0.2 (C0 2 H) 2 .H 2 0 requires C, 56.44; H, 5.86; N, 9.75%. EXAMPLE 6 1- .2-Phenylethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine hydrogen oxalate Step A: 4-(5-Methyl-4-phenyl-lH-pyrazol-3-ylmethyl) - piperazin-1-carboxylic acid tert-butylester Carrying out Steps la-c whilst replacing benzylpiperazine in Step la with tert-butyl-1-piperazine carboxylate afforded the required compound. "^H NMR (250MHz, CDC1 3 ) <S 1.45 (9H, s) , 2.32 (3H, s) , 2.36-2.52 (4H, m) , 3.35-3.70 (4H, m) , 3.39 (2H, s) , 7.25-7.45 (5H, m) . Step B: 1- .2-Phenylethyl) -4- .5-methyl-4-phenyl-lH- pyrazol-3-ylmethyl) -piperazine hydrogen oxalate To the foregoing protected piperazine (400mg, l.lmmol) in dichloromethane (10ml) was added trifluoroacetic acid (0.9ml, llmmol) . The solution was stirred at ambient temperature for 5 hours then the solvent was removed. The residue was dissolved in dichloromethane (10ml) and N,N-diisopropylethylamine (1ml, 5.75mmol) was added followed by l-phenyl-2-bromoethane (0.58ml, 3.6mmol). The solution was stirred at room temperature overnight then quenched with a saturated aqueous sodium hydrogen carbonate solution (20ml) . The organic layer was separated and the aqueous extracted with dichloromethane (2 x 30ml) . The combined organics were dried (sodium sulphate) , evaporated and purified by column chromatography on silica using dichloromethane/methanol gradient to afford the title compound free base (73mg, 18%). The hydrogen oxalate salt had mp 190-194°C. 1 H NMR (360MHz, DMSO) δ 2.21 (3H, s) , 2.55-2.65 (4H, m) , 2.8-2.94 (8H, m) , 3.59 (2H, s) , 7.2-7.4 (10H, m) . MS, CI + m/z = 361 for (M+H) + . Found: C, 63.78; H, 6.43; N, 11.55. C 23 H 28 N 4 .1.4 (C0 2 H) 2 requires C, 63.69; H, 6.38; N, 11.52%. EXAMPLE 7 3-f4- .5-Methyl-4-phenyl-lH-pyrazol-3-ylmethyl. -piperazin- 1-ylmethyl ,-lH-pyrrolo.2 ,3-blPyridine Step A: 3-Dimethylaminomethyl-lH-pyrrolor2 ,3-blpyridine A mixture of lH-pyrrolo[2, 3-b]pyridine (18.07g, 153mmol) , dimethylamine hydrochloride (13.11g, 161mmol) and paraformaldehyde (4.92g, l64mmol) in n-butanol (500ml) was heated at reflux for 35 minutes. The mixture was allowed to cool overnight and the precipitated solid collected by filtration. The filtrate was evaporated and the residue triturated with ethyl acetate to afford a second solid. The solids were combined, suspended in saturated aqueous potassium carbonate solution (500ml) and extracted with dichloromethane (twice) . The combined extracts were washed with saturated potassium carbonate (250ml) then saturated sodium chloride solution (500ml) , dried (magnesium sulphate) then evaporated to a small volume, with the product crystallising out of solution during evaporation. Diethyl ether was added and the title compound collected as a solid (18.13g, 67%) . 1 H NMR (360MHz, DMSO) <5 2.19 (6H, s) , 3.61 (2H, s) , 7.03 (1H, dd, J! = 5, J 2 = 8Hz) , 7.36 (1H, d, J = 2Hz), 8.00 (1H, dd, J λ = 2, J 2 = 8Hz), 8.20 (1H, dd, Jl = 2, J2 = 5Hz), 11.47 (1H, broad s) . Step B: 3-r4-(5-Methyl-4-phenyl-lH-pyrazol-3-ylmethyl.- piperazin-l-ylmethyl-lH-pyrrolo| " 2 ,3-b]pyridine 4-(5-Methyl-4-phenyl-lH-pyrazol-3-ylmethyl)-piperazin-1- carboxylic acid tert-butylester (365mg, lmmol) and trifluoroacetic acid (1.58ml, 20mmol) in dichloromethane (10ml) were stirred at room temperature overnight. 10% Potassium carbonate aqueous solution (40ml) was added and the organic layer separated. The aqueous solution was extracted with dichloromethane (7 x 20ml) and the combined organics dried (sodium sulphate) and evaporated. The residue and 3-dimethylaminoethyl-lH-pyrrolo[2,3-b]- pyridine (180mg, lmmol) were dissolved in toluene and heated at reflux for 31 hours. A precipitate formed on standing which was filtered and triturated with ethyl acetate to afford the required compound (245mg, 56%) mp 154-156°C. ~ ~ H NMR (360MHz, CDC1 3 ) δ 2.30 (3H, s) , 2.4- 2.6 (8H, m) , 3.56 (2H, s) , 3.69 (2H, s) , 7.05 (1H, dd, J λ = 2, J 2 = 8HZ ), 7.17 (1H, s) , 7.22-7.41 (6H, m) , 8.03 (1H, dd, J x = 2, J 2 = 8Hz ), 8.28-8.32 (1H, m) , 9.96 (1H, s) . MS, CI + m/z = 387 for (M+H) + . Found: C, 71.07; H, 6.84; N, 19.59. C 23 H 26 N 6 .0.3C 7 H 8 .0.6H 2 0 requires C, 70.94; H, 7.02; N, 19.78%. EXAMPLE 8 l-Benzyl-4-f1, 3-dimethyl-4-phenyl-lH-pyrazol-5-ylmethyl) - piperazine bis hydrogen oxalate Carrying out Steps la-c whilst replacing hydrazine hydrate in Step lc with methylhydrazine afforded the titled compound free base. The bis hydrogen oxalate salt had mp 196-198°C. ^-H NMR (360MHz, DMSO) δ 2.08 (3H, s) , 2.37-2.62 (4H, m) , 2.81-2.99 (4H, m) , 3.52 (2H, s) , 3.80 (3H, s) , 4.04 (2H, ε) , 7.22-7.51 (10H, m) . MS, CI + m/z = 361 for (M+H) + . Found: C, 58.84; H, 6.01; N, 10.20. 23 H 28 N 4- 2 ( co 2 H )2-°- 5H 2° requires C, 59.01; H, 6.05; N, 10.19%. EXAMPLE 9 l-Benzyl-4- (l-methyl-4-phenyl-lH-pyrazol-3-ylmethyl. - piperazine bis hydrogen oxalate Carrying out Steps la-c whilst replacing acetic acid in Step lb with formic acid and hydrazine hydrate in Step lc with methyl hydrazine afforded a mixture of titled compound and itε regioisomer. The mixture was purified by column chromatography on silica using dichloromethane/methanol gradient to yield the required compound free base. The bis hydrogen oxalate had mp 222- 225 ,, C. ^-H NMR (360MHz, DMSO) δ 2.66-3.02 (8H, m) , 3.74 (2H, s) , 3.85 (3H, s) , 3.97 (2H, s) , 7.22-7.57 (10H, m) , 7.98 (1H, ε) . MS, CI + m/z = 347 for (M+H) + . Found: C, 56.35; H, 5.75; N, 9.71. C 22 H 26 N 4 .2 (C0 2 H) 2 .1.5H 2 0 requires C, 56.41; H, 6.01; N, 10.12%. EXAMPLE 10 l-Benzyl-4-f2-methyl-4-phenyl-2H-pyrazol-3-ylmethyl. - piperazine biε hydrogen oxalate The title compound was obtained using the procedure described in Example 9. The bis hydrogen oxalate had mp 214-217°C. 1 H NMR (360MHz, DMSO) δ 2.50-3.10 (8H, m) , 3.69 (2H, s) , 3.88 (3H, s) , 4.07 (2H, ε) , 7.23-7.48 (10H, m) , 7.58 (1H, ε) . MS, CI + m/z = 347 for (M+H) + . Found: C, 55.42; H, 5.51; N, 9.24. C 22 H 26 N 4 .2.25(C0 2 H) 2 .1.5H 2 0 requires C, 55.26; H, 5.86; N, 9.73%. EXAMPLE 11 l-Benzyl-4- , 5 ( 3 ) -methyl-4-phenyl-isoxazol-3 (5) -ylmethyl) - piperazine bis hydrogen oxalate A solution of l-(4-benzylpiperazin-l-yl) -3-phenyl-pentan- 2,4-dione (4.55g, 13mmol) , hydroxyla ine hydrochloride (3.64g, 52mmol) and N,N-diisopropylethylamine (9.2ml, 52mmol) and N,N'-dimethyl forma ide (80ml) was heated at 60°C for 5 hours, cooled to ambient temperature, diluted with water (50ml) and extracted with ethyl acetate (2 x 50ml) . The combined organics were dried (sodium sulphate) and evaporated. To the residue in dichloromethane (100ml) at 0°C was added methanesulphonyl chloride (1.5ml, 19mmol) and triethylamine (4ml, 26mmol) . The solution was stirred at room temperature overnight then quenched with water. The organic layer was separated, washed with brine, dried (sodium εulphate) and evaporated. The reεidue waε purified by column chromatography on silica using methanol/dichloromethane gradient and recrystallised from ethyl acetate. The bis hydrogen oxalate salt (201mg, 4.4%) had mp 206-207°C. 1 H NMR (360MHz, MeOH/D 2 0) δ 2.26 (3H, ε) , 2.64-2.94 (4H, m) , 3.1-3.28 (4H, m) , 3.82 (2H, ε) , 4.29 (2H, ε) , 7.35-7.51 (10H, m) . MS, CI + m/z = 348 for (M+H) + . Found: C, 59.00; H, 5.37; N, 7.59. C 22 H 25 N 3 0.2 (C0 2 H) 2 requireε C, 59.20; H, 5.54; N, 7.97%. EXAMPLE 12 l-Benzyl-4-r4-(4-chlorophenyl) -5-methyl-lH-Pyrazol-3- ylmethyl1-piperazine biε hydrogen oxalate Step A: l-Chloro-3-(4-chlorophenyl)-propan-2-one The title compound waε prepared following a literature procedure (Eur. J. Med. Chem. Chimica Therapeutica. 1979, 14(2), 165) and had mp 61-63°C. ^Η NMR (250MHz, CDC1 3 ) δ 3.82 (2H, ε) , 4.04 (2H, s) , 7.07-7.32 (4H, ) . Step B: l-Benzyl-4-r4-(4-chlorophenyl) -5-methyl-lH- pyrazol-3-ylmethyll-piperazine bis hydrogen oxalate The title compound was obtained using the procedure described in Example 1 using l-chloro-3- (4-chlorophenyl) - propan-2-one for l-chloro-3-phenyl-propan-2-one in Step la. The bis hydrogen oxalate had mp 232-233 °C. NMR (360MHz, DMSO) δ 2.33 (3H, s) , 2.65-2.95 (8H, m) , 3.68 (2H, s) , 3.90 (2H, s) , 7.35-7.50 (9H, m) . MS, CI + m/z = 381 for (M+H) + . Found: C, 54.97; H, 5.10; N, 9.74. C 22 H 25 N 4 C1.2(CO 2 H) 2 .0.4H 2 O requireε C, 54.96; H, 5.29; N, 9.56%. EXAMPLE 13 l-Benzyl-4-[5-methyl-4- .2-methylphenyl) -lH-pyrazol-3- ylmethyl]-piperazine bis hydrogen oxalate Step A: l-Chloro-3- (2-methylphenyl . -propan-2-one The title compound was prepared following a literature procedure .Eur. J. Med. Chem. Chimica Therapeutica, 1979, 14(2) , 165) . 1 H NMR (250MHz, CDC1 3 ) <_ 2.28 (3H, s) , 3.92 (2H, ε) , 4.13 (2H, ε) , 7.10-7.34 (4H, m) . Step B: l-Benzyl-4-f5-methyl-4- (2-methylphenyl) -1H- pyrazol-3-ylmethyll-piperazine bis hydrogen oxalate The title compound was obtained following the procedure described in Example 1 using l-chloro-3- (2-methylphenyl) - propan-2-one instead of l-chloro-3-phenyl-propan-2-one in Step la and by heating the reaction under refluxing conditions overnight before quenching the reaction in Step lb. The bis hydrogen oxalate εalt had mp 220-221°C. NMR (360MHz, DMSO) δ 2.00 (3H, s) , 2.04 (3H, ε) , 2.60- 2.9 (8H, m) , 3.54-3.80 (2H, m) , 3.79 (2H, ε) , 7.08-7.44 (9H, m) . MS, CI + m/z = 361 for (M+H) + . Found: C, 58.85; H, 6.00; N, 10.17. C 23 H 28 N 4 .2 (C0 2 H) 2 .0.5H 2 0 requires C, 59.01; H, 6.05; N, 10.19%. EXAMPLE 14 l-(3-Chlorobenzyl) -4- .5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl, -piperazine biε hydrogen oxalate Step A: 1-(3-Chlorobenzyl. -piperazine The title compound waε obtained following the procedure deεcribed in Stepε 4a-b using 3-chlorobenzyl bromide instead of 4-chlorobenzyl chloride in Step 4a. ■ ' ■ H NMR (360MHz, CDC1 3 ) <δ 2.60-2.72 (4H, m) , 3.03-3.14 (4H, m) , 3.65 (2H, s) , 7.16-7.44 (4H, m) . Step B: 1—f4—f3-Chlorobenzyl, -piperazin-1-yll-3-phenyl- propan-2-one To a solution of l-chloro-3-phenyl-propan-2-one (2g, 11.9mmol) in dichloromethane (30ml) was added l-(3- chlorobenzyl) -piperazine (2.5g, 11.9mmol) and triethyla ine (0.82ml, 11.9mmol). The εolution waε stirred overnight at ambient temperature and a 15% aqueous solution of potassium carbonate (20ml) waε added. The organic phaεe was decanted and extracted with 2M hydrochloric acid (50ml) . The acidic layer was separated, basified with potassium carbonate and extracted with dichloromethane (2 x 50ml) . The combined organics were treated with sodium sulphate, potassium carbonate and silica (Kieselgel) . The mixture was filtered then evaporated to drynesε to afford the required compound as an oil (800mg, 19%) . -^H NMR (360MHz, CDC1 3 ) δ 2.40-2.58 (8H, m) , 3.20 (2H, s) , 3.48 (2H, s) , 3.73 (2H, ε) , 7.20-7.36 (9H, m) . Step C: l-(3-Chlorobenzyl. -4- ,5-methyl-4-phenyl-lH- pyrazol-3-ylmethyl)-piperazine biε hydrogen oxalate Carrying out Step lb-c whilεt replacing l-(4- benzylpiperazin-l-yl)-3-phenyl-propan-2-one in Step lb with l-[4-(3-chlorobenzyl) -piperazin-l-yl]-3-phenyl- propan-2-one afforded the titled compound aε a solid, mp 233-235 <> C. ^-H NMR (360MHz, DMSO) <5 2.24 (3H, s) , 2.60- 3.00 (8H, m) , 3.71 (2H, s) , 3.89 (2H, ε) , 7.26-7.48 (9H, m) . MS, CI + m/z = 381 for (M+H) + . Found: C, 54.45; H, 4.87; N, 9.52. C 22 H 25 N 4 C1.2 (C0 2 H) 2 .0.5H 2 0 requireε C, 54.79; H, 5.30; N, 9.83%. EXAMPLE 15 1-(2-Methylbenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine bis hydrogen oxalate Carrying out Steps 14a-c whilst replacing 3-chlorobenzyl bromide in Step 14a with 2-methylbenzyl bromide and stirring the solution two hours at reflux instead of overnight at ambient temperature in Step 14b afforded the titled compound as a εolid. mp 225-228°C. 1 H NMR (360MHz, DMSO) δ 2.23 (3H, ε) , 2.31 (3H, ε) , 2.66-3.00 (8H, m) , 3.69 (2H, s) , 3.89 (2H, s) , 7.13-7.47 (9H, m) . MS, CI + m/z = 361 for (M+H) + . Found: C, 59.79; H, 6.02; N, 10.32. C 23 H 28 N 4 .2(C0 2 H) 2 requires C, 59.99; H, 5.96; N, 10.36%. EXAMPLE 16 l-(2-Chlorobenzyl) -4- (5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine biε hydrogen oxalate The titled compound was obtained following procedure described in Example 15 using 2-chlorobenzyl chloride for 2-methylbenzyl bromide. mp 219-221°C. ^-H NMR (360MHz, DMSO) <5 2.24 (3H, s) , 2.60-2.76 (4H, m) , 2.84-3.06 (4H, m) , 3.67 (2H, s) , 4.02 (2H, s) , 7.27-7.52 (9H, ) . MS, CI + m/z = 381 for (M+H) + . Found: C, 55.15; H, 5.04; N, 9.88. C 22 H 25 N 4 C1.2(CO 2 H) 2 .0.2H 2 O requires C, 55.31; H, 5.25; N, 9.92%. EXAMPLE 17 1-fPyridin-4-ylmethyl) -4- (5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)-piperazine bis hydrogen oxalate Carrying out Steps 14a-c whilst replacing 3-chlorobenzyl bromide in Step 14a with 4-picolyl chloride hydrochloride afforded the titled compound as a solid. mp 186-189°C. 1 H NMR (360MHz, DMSO) δ 2.24 (3H, s) , 2.77-2.96 (8H, m) , 3.82 (2H, ε) , 3.95 (2H, ε) , 7.28-7.48 (7H, m) , 7.80-7.88 (1H, m) , 8.52-8.60 (1H, m) . MS, CI + m/z = 348 for (M+H) + . Found: C, 54.70; H, 5.14; N, 12.37. C 21 H 25 N 5 .2.2 (CO 2 H) 2 .0.5H 2 O requireε C, 55.01; H, 5.52; N, 12.63%. EXAMPLE 18 l-.Pyridin-3-ylmethyl)-4- .5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl) -piperazine biε hydrogen oxalate Carrying out Stepε 14a-c whilεt replacing 3-chlorobenzyl bromide in Step 14a with 3-picolyl chloride hydrochloride afforded the titled compound aε a solid, mp 212-215°C. ^ ■ H NMR (360MHz, DMSO) δ 2.24 (3H, s) , 2.60-3.02 (8H, m) , 3.75 (2H, ε) , 3.91 (2H, s) , 7.28-7.48 (6H, m) , 7.72-7.79 (1H, m) , 8.50-8.56 (2H, m) . MS, CI + m/z = 348 for (M+H) + . Found: C, 54.56; H, 5.34; N, 12.37. C 21 H 25 N 5 .2.1(C0 2 H) 2 .H 2 0 requires C, 54.38; H, 5.67; N, 12.63%. EXAMPLE 19 1-(Pyridin-2-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)-piperazine bis hydrogen oxalate Carrying out Steps 14a-c whilεt replacing 3-chlorobenzyl bromide in Step 14a with 2-picolyl chloride hydrochloride afforded the titled compound aε a εolid. mp 209-211"C. 1 H NMR (360MHz, DMSO) δ 2.24 (3H, ε) , 2.56-2.70 (4H, m) , 2.84-3.02 (4H, m) , 3.61 (2H, ε) , 3.97 (2H, s) , 7.30-7.48 (7H, m) , 8.48-8.54 (2H, m) . MS, CI + m/z = 348 for (M+H) + . Found: C, 55.66; H, 5.75; N, 12.94. C 21 H 25 N 5 .2 (CO 2 H) 2 .0.5H 2 O requires C, 55.96; H, 5.64; N, 13.05%. EXAMPLE 20 l-Benzyl-4-(4-(2-methylphenyl) -lH-pyrazol-3-ylmethyl)- piperazine biε hydrogen oxalate Carrying out Steps la-c whilεt replacing l-chloro-3- phenyl-propan-2-one with l-chloro-3-(2-methylphenyl)- propan-2-one in Step lb and acetic acid with formic acid in Step lc afforded the titled compound. The bis hydrogen oxalate had mp > 200°C. ^-H NMR (360MHz, DMSO) <S 2.17 (3H, s) , 2.60-2.94 (8H, m) , 3.71 (2H, ε) , 3.85 (2H, ε) , 7.18-7.44 (9H, m) , 7.73 (1H, ε) . MS, CI + m/z = 347 for (M+H) + . Found: C, 57.79; H, 5.68; N, 10.06. C 22 H 26 N 4 .2(CO 2 H) 2 .0.8H 2 O requireε C, 57.73; H, 5.89; N, 10.36%. EXAMPLE 21 l-(2-Chlorobenzyl) -4-.5C3) -methyl-4-phenyl-iεoxazol-3 (5) - ylmethyl) -piperazine biε hydrogen oxalate Step A: 1- (2-Chlorobenzyl)-piperazine The title compound waε obtained following the procedureε described in Step 4a-b using 2-chlorobenzyl chloride instead of 4-chlorobenzyl chloride in Step 4a. -^H NMR (360MHz, CDC1 3 ) δ 2.44-2.64 (8H, m) , 3.19 (2H, s) , 3.63 (2H, s) , 3.74 (2H, ε) , 7.12-7.48 (4H, m) . Step B: 1- I4- (2-Chlorobenzyl)-piperazin-1-yll-3-phenyl- pentan-2 , 4-dione The required compound waε obtained carrying out Steps la- b whilεt replacing benzylpiperazine in Step la with l-(2- chlorobenzyl) -piperazine. The dione waε used crude in the next step. Step C: l-f2-Chlorobenzyl) -4-(5(3) -methyl-4-phenyl- iεoxazol-3 (5)-ylmethyl)-piperazine biε hydrogen oxalate The titled compound waε prepared following the procedures described in Example 11 using the foregoing diketone instead of 1-(4-benzylpiperazin-l-yl)-3-phenyl-pentan- 2,4-dione. The bis hydrogen oxalate had mp 204-207°C. ϊl NMR (360MHz, DMSO) <5 2.23 (3H, ε) , 2.48-2.60 (4H, m) , 2.68-2.80 (4H, m) , 3.72 (2H, s) , 3.87 (2H, s) , 7.34-7.58 (9H, m) . MS, CI + m/z = 382 for (M+H) + . Found: C, 54.58; H, 5.05; N, 7.22. C 22 H 24 N 3 0C1.2 (C0 2 H) 2 .0.5H 2 0 requires C, 54.69; H, 5.12; N, 7.36%. EXAMPLE 22 1- , 2-Methylbenzyl) -4-(5(3) -methyl-4-phenyl-isoxazol-3 (5) - ylmethyl)piperazine bis hydrogen oxalate Carrying out Steps 21a-c whilεt replacing 2-chlorobenzyl chloride in Step 21a with 2-methylbenzyl bromide afforded the titled compound aε a εolid. mp 204-207°C. 1 H NMR (360MHz, DMSO) δ 2.22 (3H, ε) , 2.31 (3H, ε) , 2.50-2.64 (4H, m) , 2.78-2.94 (4H, m) , 3.70 (2H, ε) , 3.92 (2H, ε) , 7.17-7.52 (9H, m) . MS, CI + m/z = 362 for (M+H) + . Found: C, 57.69; H, 5.49; N, 7.99. C 23 H 27 N 3 0. 2 .1 (C0 2 H) 2 .0.7H 2 0 requires C, 58.01; H, 5.83; N, 7.46%. EXAMPLE 23 1-(Pyridin-3-ylmethyl) -4- (5 ( 3) -methyl-4-phenyl-isoxazol- 3 (5) -ylmethyl) -piperazine bis hydrogen oxalate Carrying out Steps 2la-c whilεt replacing 2- chlorobenzylchloride in Step 21a with 3-picolyl chloride hydrochloride afforded the title compound. mp 197-200°C. X H NMR (360MHz, DMSO) δ 2.23 (3H, s) , 2.44-2.64 (4H, m) , 2.68-2.86 (4H, m) , 3.69 (2H, s) , 3.91 (2H, ε) , 7.36-7.56 (6H, m) , 7.76-7.84 (1H, m) , 8.50-8.59 (2H, ) . MS, CI + m/z = 349 for (M+H) + . Found: C, 55.52; H, 5.12; N, 10.00. C 21 H 24 N 4 0.2 (C0 2 H) 2 .0.5H 2 O requireε C, 55.86; H, 5.44; N, 10.42%. EXAMPLE 24 l-(4-methylbenzyl) -4-r5-methyl-4- (2-methylphenyl) -1H- pyrazol-3-ylmethyll-piperazine bis hydrogen oxalate Step A: 1-f4-methylbenzyl) -piperazine The title compound was obtained following the procedure described in stepε 4a-b uεing 4-methylbenzyl chloride instead of 4-chlorobenzyl chloride in Step 4a. 1 H NMR (360MHz, CDC1 3 ) <5 2.33 (3H, s) , 2.40-2.55 (4H, m) , 2.90- 3.00 (4H, ) , 3.51 (2H, ε) , 7.12 (2H, d, J = 8Hz) , 7.19 (2H, d, J = 8Hz) . Step B: 1- \ 4- (4-methylbenzyl) -piperazin-l-yll-3- ( 2- methylphenyl) -propan-2-one The title compound waε obtained following the procedure deεcribed in Step 14b using l-chloro-3-(2-methylphenyl)- propan-2-one instead of l-chloro-3-phenyl-propan-2-one. - T5 - 1 H NMR (360MHZ, DMSO) δ 2.26(3H, s) , 2.33 (3H, s) , 2.47- 2.60 (8H, m) , 3.16 (2H, s) , 3.48(2H, s) , 3.75(2H, s) , 7.04-7.20(8H, m) . MS, ES + m/z=337 for (M+H) + . Step C: 1-(4-methylbenyl)-4-r5-methyl-4-(2-methylphenyl)- lH-pyrazol-3-ylmethyll-piperazine bis hydrogen oxalate Carrying out step lb-c whilst replacing l-(4- benzylpiperazin-l-yl)-3-phenyl-propan-2-one in step lb with l-[4-(3-methylbenzyl) -piperazin-l-yl]-3-(2- methylphenyl) -propan-2-one afforded the title compound as a εolid, mp 216-218°C. ^-H NMR (360MHz, DMSO) δ 2.00 (3H, ε) , 2.04 (3H, ε) , 2.22 (3H, ε) , 2.60-2.86 (8H, m) , 3.51 (1H, d, J = 13Hz), 3.67 (1H, d, J = 13Hz), 3.81 (2H, s) , 7.05-7.30 (8H, m) . MS, ES + m/z=375 for (M+H) + . Found: C, 59.05; H, 5.77; N, 9.50. C 2 H 30 N .2.3 (C0 2 H) 2 requireε C, 59.06; H, 5.99; N, 9.63%o # EXAMPLE 25 1-(4- ethylbenzy1) -4-f5 (3)-methyl-4-(2-methylphenyl) - isoxazol-3 (5) -ylmethyl]-piperazine bis hydrogen oxalate Step A: 1-[4- (4-methylbenzyl)-piperazin-1-yll-3-(2- methylphenyl)pentan-2 ,4-dione The required compound was obtained carrying out Step lb whilεt replacing 1-(4-benzylpiperazin-l-yl) -3-phenyl- propan-2-one with l-[4-(4-methylbenzyl) -piperazin-1-yl]- 3-(2-methylphenyl) -propan-2-one. The dione was uεed crude in the next εtep. Step B: 1- (4-methylbenzyl) -4-r5 (3) -methyl-4- ( 2- methylphenyl) -isoxazol-3 C5) -ylmethyl1-piperazine bis hydrogen oxalate The title compound was prepared following the procedure described in Example 11 using the foregoing diketone instead of l-(4-benzylpiperazin-l-yl) -3-phenyl-pentan- 2,4-dione. The bis hydrogen oxalate had mp. 197-198°C. K NMR (360MHz, DMSO) δ 2.02 (3H, s) , 2.07 (3H, s) , 2.31 (3H, s) , 2.70-2.95 (8H, m) , 3.45 (1H, d, J = 13Hz) , 3.62 (1H, d, J = 13Hz), 4.00 (2H, s) , 7.08-7.36 (8H, m) . MS, ES + m/z=376 for (M+H) + . Found: C, 60.55; H, 5.91; N, 7.32. C 24 H 29 N 3 0.2 (C0 2 H) 2 requires C, 60.53; H, 5.99; N, 7.56%.

Claims: CLAIMS : 1. A compound of formula I, or a salt thereof or a prodrug thereof: ( I) wherein the broken circle representε two non-adjacent double bonds whereby the five-membered ring containing X and Y is aromatic; one of X and Y representε nitrogen, and the other of X and Y repreεentε oxygen or N-R 5 ; R 1 repreεentε hydrogen, C^_ alkyl or trifluoromethyl; R and R independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluorom a , -SR a , -S0R a , -S0 2 R a , -S0 2 NR ,a α n Rb , , -NR α C0 2 R iJ , -C0R α , -C0 2 R α or -CONR a R b R 4 represents hydrocarbon or a heterocyclic group; R 5 represents hydrogen or ~ - - alkyl; and R R aa aanndd RR iinnddeeppeennddeennttllyy rreepresent hydrogen, hydrocarbon or a heterocyclic group. 2. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof: 12 ( I IA) wherein R 1 is as defined in claim 1; X 1 repreεentε oxygen or N-R in which R 5 iε as defined in claim 1; R representε hydrogen, halogen, cyano, trifluoromethyl, nitro, amino, ~ ~_-ς, alkylamino, di(C^g)alkylamino, C^-g alkyl, C^-g alkoxy, aryl(Cι_g)alkoxy or C 2 _g alkylcarbonyl; n iε 1, 2, 3 or 4 ; and W repreεents a group of formula (i) or (ii) : ( i ) (N) in which Z representε nitrogen or CH; and R 16 repreεents hydrogen, halogen, nitro, C^-g alkyl or C^ ^ .g alkoxy, 3. A compound aε claimed in claim 1 repreεented by formula IIB, and εaltε and prodrugε thereof: ( I IB) wherein Rι lε aε defi.ned in claim 1; Y represents oxygen or N-R 5 in which R 5 is as defined in claim 1; and R , n and W are as defined in claim 2. 4. A compound as claimed in claim 2 or claim 3 wherein R represents hydrogen, methyl, ethyl, isopropyl, nitro, methoxy or chloro. 5. A compound as claimed in any one of clai ε 2 to 4 whe.rreeiinn RR l 1 e x represents hydrogen, chloro, nitro, methyl or methoxy. A compound as claimed in claim 1 selected from: l-benzyl-4- (5-methyl-4-phenyl-lH-pyrazol-3-ylmethyl) - piperazine; l-benzyl-4-(5-ethyl-4-phenyl-lH-pyrazol-3-ylmethyl) - piperazine; l-benzyl-4-(4-phenyl-lH-pyrazol-3-ylmethyl)piperazine; 1-(4-chlorobenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; 1-(4-methoxybenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; 1-(2-phenylethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; 3-[4-(5-methyl-4-phenyl-lH-pyrazol-3-ylmethyl)piperazin- 1-ylmethyl]-lH-pyrrolo[2,3-b]pyridine; l-benzyl-4-(l, 3-dimethyl-4-phenyl-lH-pyrazol-5-ylmethyl) piperazine; l-benzyl-4-(l-methyl-4-phenyl-lH-pyrazol-3-ylmethyl)- piperazine; l-benzyl-4-(2-methyl-4-phenyl-2H-pyrazol-3-ylmethyl) - rptiϊ Tp-_ee-.Tr~a__7.z_7i"i nnoe;• l-benzyl-4-(5 (3) -methyl-4-phenylisoxazol-3 (5) -ylmethyl) - piperazine; l-benzyl-4-[4-(4-chlorophenyl) -5-methyl-lH-pyrazol-3- ylmethy1]piperazine; l-benzyl-4-[5-methyl-4-(2-methylphenyl) -lH-pyrazol-3- ylmethy1]piperazine; l-(3-chlorobenzyl)-4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; l-(2-methylbenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; l-(2-chlorobenzyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; l-(pyridin-4-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; 1-(pyridin-3-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethy1)piperazine; 1- (pyridin-2-ylmethyl) -4-(5-methyl-4-phenyl-lH-pyrazol-3- ylmethyl)piperazine; l-benzyl-4-[4-(2-methylphenyl) -lH-pyrazol-3-ylmethyl]- piperazine; 1-(2-chlorobenzyl) -4-(5(3) -methyl-4-phenylisoxazol-3 (5) - ylmethyl)piperazine; 1-(2-methylbenzyl) -4-(5(3) -methyl-4-phenylisoxazol-3 (5) - ylmethyl)piperazine; 1-(pyridin-3-ylmethyl) -4-(5(3) -methyl-4-phenylisoxazol- 3(5) -ylmethyl)piperazine; 1-(4-methylbenzy1) -4-[5-methy1-4-(2-methylphenyl) -1H- pyrazol-3-ylmethyl]piperazine; 1-(4-methylbenzyl) -4-[5(3) -methyl-4-(2- methylphenyl) isoxazol-3 (5) -ylmethyl]piperazine; and saltε and prodrugε thereof. 7. A pharmaceutical compoεition compriεing a compound aε claimed in any one of the preceding claimε in association with a pharmaceutically acceptable carrier. 8. A compound as claimed in any one of claimε 1 to 6 for uεe in therapy. 9. The use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment and/or prevention of disorderε of the dopamine system. 10. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a compound of formula III with a compound of formula IV: ( H I ) ( IV) wherein R 1 , R 2 and R 3 are as defined in claim 1, R 40 correεponds to the group R as defined in claim 1 or representε an amino-protecting group, and X a repreεentε oxygen or N-R 5 in which R is as defined in claim 1; followed, where necessary, by removal of the amino- protecting group R 40 and subεequent attachment of the εubεtituent R ; and εubεequently, if deεired, converting a compound of formula I initially obtained into a further compound of formula I by conventional methodε. 11. A method for the treatment and/or prevention of diεorders of the dopamine system, which method compriseε administering to a patient in need of such treatment an effective amount of a compound as claimed in any one of claims 1 to 6.

Inventors: BOURRAIN SYLVIE, LEESON PAUL, NEDUVELIL JOSEPH, SHOWELL GRAHAM, BOURRAIN, SYLVIE, LEESON, PAUL, NEDUVELIL, JOSEPH, SHOWELL, GRAHAM
Applicants: BOURRAIN SYLVIE, LEESON PAUL, MERCK SHARP & DOHME, NEDUVELIL JOSEPH, SHOWELL GRAHAM, BOURRAIN, SYLVIE, LEESON, PAUL, MERCK SHARP & DOHME LIMITED, NEDUVELIL, JOSEPH, SHOWELL, GRAHAM
Application year: 1994
Main classification: C07D231
IPC codes: C07D231, C07D261, C07D401, C07D471